Protection From Receptor Mediated Apoptotic Signaling

Apoptosis can be triggered by various receptor ligand interactions and intracellular events.77-82 Trimerization of cell surface tumor necrosis factor receptor (TNFR) and Fas are the two principal mechanisms by which lymphocytes induce apoptosis in immune responses to intracellular pathogens and tumor surveillance. Recognition of TNF and FasL, respectively, by these cell surface complexes can trigger a caspase cascade that results in the cleavage of death substrates and, ultimately, nuclear fragmentation and partitioning of the cell into apoptotic bodies. There are a few interesting characteristics of each of the mechanisms. The TNFR can also trigger a signaling cascade that results in activation of transcription factors (such as NF-kB and

Figure 12-9. Tax mediates constitutive activation of IL-2 signaling pathways. HTLV Tax has the ability to activate NF-kB, which trans-activates genes for IL-2 and the IL-2 receptor-alpha chain. In HTLV-infected cells these two proteins are hyperexpressed, causing high surface expression of the IL-2 receptor and a high extracellular concentration of IL-2, which can act as an autocrine factor. IL-2 binding to its cognate receptor transduces a signaling pathway, involving recruitment and phosphorylation of specific members of the Janus family tyrosine kinases (JAKs), and subsequent phosphorylation of specific members of the signal transducers and activators of transcription (STATs) family of transcription factors. This pathway results in the formation of active STAT homo- and het-erodimers that can activate the transcription of the IL-2 response genes, which are responsible for cell cycle progression and growth. In HTLV-infected T cells, this pathway would be hyperactive, and would stimulate the cell to proceed through the cell cycle and proliferate in the absence of either direct or indirect antigenic stimulation. (Adapted from Leonard and O'Shea,56 with permission.)

Figure 12-9. Tax mediates constitutive activation of IL-2 signaling pathways. HTLV Tax has the ability to activate NF-kB, which trans-activates genes for IL-2 and the IL-2 receptor-alpha chain. In HTLV-infected cells these two proteins are hyperexpressed, causing high surface expression of the IL-2 receptor and a high extracellular concentration of IL-2, which can act as an autocrine factor. IL-2 binding to its cognate receptor transduces a signaling pathway, involving recruitment and phosphorylation of specific members of the Janus family tyrosine kinases (JAKs), and subsequent phosphorylation of specific members of the signal transducers and activators of transcription (STATs) family of transcription factors. This pathway results in the formation of active STAT homo- and het-erodimers that can activate the transcription of the IL-2 response genes, which are responsible for cell cycle progression and growth. In HTLV-infected T cells, this pathway would be hyperactive, and would stimulate the cell to proceed through the cell cycle and proliferate in the absence of either direct or indirect antigenic stimulation. (Adapted from Leonard and O'Shea,56 with permission.)

AP-1) that cause cell cycle progression. Fas can trigger two separate pro-apoptotic cascades each of which result in the activation of caspase 3, the principal effector caspase, and cell death.

Tax activates IKKs and promotes the dissociation and degradation of IkB and trans-activates the cJun gene.46'47 Tax has also been shown to trans-activate the XIAP gene, which is an activated caspase 3 inhibitor, and presumably trans-activates a

FLICE inhibitory protein (FLIP) preventing the activation of caspase 8.83 Tax inhibits the mitochondria-associated apoptotic pathway by trans-suppressing Bax and trans-activating the Bcl-Xl gene via NF-kB activation, increasing the Bcl-Xl:Bax ratio.84,85 This prevents the dissociation of Apaf-1, a necessary substituent of the active caspase 9 complex, from the mito-chondrial membrane resulting in protection from apoptosis.

Figure 12-10. Inactivation of retinoblastoma protein by HTLV-1 Tax. The unphosphorylated form of the retinoblastoma (Rb) protein is a tumor suppressor that sequesters E2F-1, a transcriptional activator responsible for cell cycle progression, in the cytoplasm. The ability of Rb to act as a tumor suppressor is dependent on the cyclin-dependent kinase inhibitor p16ink4a (and members of the same family). This inhibitor prevents the phosphorylation of Rb by inhibiting the activity of CDK4, a cyclin-dependent kinase. HTLV Tax can physically associate with p16ink4a and prevent it from inhibiting CDK4. In the presence of Tax there is no mechanism to prevent the phos-phorylation of Rb. In its constitutively phosphorylated form, Rb cannot sequester E2F-1, resulting in the unchecked activation of E2F-1, and the breakdown of tumor suppression.

Figure 12-10. Inactivation of retinoblastoma protein by HTLV-1 Tax. The unphosphorylated form of the retinoblastoma (Rb) protein is a tumor suppressor that sequesters E2F-1, a transcriptional activator responsible for cell cycle progression, in the cytoplasm. The ability of Rb to act as a tumor suppressor is dependent on the cyclin-dependent kinase inhibitor p16ink4a (and members of the same family). This inhibitor prevents the phosphorylation of Rb by inhibiting the activity of CDK4, a cyclin-dependent kinase. HTLV Tax can physically associate with p16ink4a and prevent it from inhibiting CDK4. In the presence of Tax there is no mechanism to prevent the phos-phorylation of Rb. In its constitutively phosphorylated form, Rb cannot sequester E2F-1, resulting in the unchecked activation of E2F-1, and the breakdown of tumor suppression.

The effects of Tax on the TNF-induced and Fas-induced apop-totic pathways are summarized in Figures 12-12 and 12-13, respectively.

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